title: Anti-androgenic activity of hydroxyxanthones in prostate cancer LNCaP cells.
abstract: Anti-androgens are used to treat prostate cancer. Here, we report that hydroxyxanthones from a plant extract act as anti-androgens in androgen receptor (AR)-positive prostate cancer LNCaP cells. Anti-androgenic activity of the ethanol extract from Garcinia subelliptica was observed in a luciferase assay using LNCaP/MMTV cells with a stably integrated mouse mammary tumor virus (MMTV) promoter. HPLC-based activity profiling followed by a chemical library-based assay strategy enabled the rapid identification of several active principles bearing a xanthone core substituted with hydroxyl and isoprenyl groups. Among the active compounds, 2-(1,1-dimethyl-allyl)-1,4,5,6-tetrahydroxyxanthone (subelliptenone F) was identified as a potent inhibitor of AR transcriptional activity. The structure-activity relationship of some substituents on the xanthone core was also determined using the chemical library-based bioassay. A quantitative RT-PCR analysis revealed that treatment with the compound resulted in a significant reduction in AR-induced gene (KLK3) expression. Hydroxyxanthone may be a possible candidate for the development of a new anti-androgenic molecule.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Shakui
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iguchi
authors.affiliation: Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ito
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Baba
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. Electronic address: usui@gifu-pu.ac.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Usui
authors.affiliation: Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Oyama
authors.affiliation: Field & Device Co., 2-1-10 Dosyo-machi, Osakashichuou-ku, Osaka 541-0045, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tosa
authors.affiliation: Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hirano
mesh_terms: D000726:Androgen Antagonists / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D029760:Garcinia / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008517:Phytotherapy; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C000591470:2-(1,1-dimethylallyl)-1,4,5,6-tetrahydroxyxanthone; D000726:Androgen Antagonists; D000972:Antineoplastic Agents, Phytogenic; D011944:Receptors, Androgen; D044004:Xanthones; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Androgen receptor; Garcinia subelliptica; Hydroxyxanthone; LNCaP